The present invention is directed to novel pharmaceutical compositions which possess immunosuppressive activity, particularly activity which modulates cell-mediated immune responses.
Suppression of the immune response is often required to prevent graft rejection (i.e., graft tolerance) following transplantation surgery. Immunosuppression is also used to inhibit an inappropriate immune response such as autoimmune diseases that often cause severe and debilitating tissue damage. In clinical use today there are natural products for use as immunosuppressants such as fungal metabolites (e.g., Cyclosporin A, FK 506) to prevent graft rejection after transplantation surgery and steroids (e.g., glucocorticosteroids and corticosteroids) to counter inflammation in some autoimmune diseases. However, the therapeutic value of drug discovery in this area would be most immediately realized in the area of organ transplantation. Since 1990 it is estimated that there are approximately 16,000 organ transplantation each year in the United States (Publication, United Network for Transplanted Organs, August 1993). The success of graft tolerance by immunosuppressant drug therapy is well established, but it will continue to require more potent, and less toxic, drugs to reduce morbidities and mortalities associated with them.
Graft tolerance following organ transplantation does not occur unless it is autologous (self) or syngeneic (i.e., between genetically identical individuals; twins); therefore, it must be induced. The immune system which normally acts to reject allogeneic grafts can be inhibited by the use of immunosuppressive drugs. Evidence has accumulated over the years to indicate that the T cell, a functionally and morphologically distinct lymphocyte, is primarily responsible for the rejection of solid grafts by a mechanism referred to as `cell-mediated`. Cell-mediated immune reactions are cell (lymphocyte)-to-cell (grafted tissue) targeted destruction in lieu of an antibody-to-cell defense. More specifically, there are subsets of T cells that most certainly act to destroy foreign tissue types. Whether cells such as cytotoxic T cells, delayed-type hypersensitivity T cells, or macrophages act alone or in combination, together with T helper cells, to elicit graft rejection remains to be more clearly delineated.
Cyclosporin A, the most prescribed post-transplantation therapeutic agent, is a T cell specific immunosuppressive compound (Cohen et al., Ann. Int. Med., 101:667 (1984)). It works to allow allogeneic graft tolerance by inhibiting normal lymphocyte function, especially T-helper cells (Th). Current data suggests that it blocks IL-2 production and secretion by these cells and, to a lesser degree, IL-1 production by macrophages, possibly inhibiting IL-2 binding to its receptor, and/or inhibiting the chemotactic activity of cyclophilins to recruit eosinophils and neutrophils (Xu et al., J. Biol. Chem., 267:11968 (1992)). Cyclosporin A, although effective, demonstrates considerable toxicity to the recipients of the drug. In particular, there is marked hepatotoxicity associated with its use. Regardless, the specificity of its action is in contrast to the actions of azathioprine metabolites and corticosteroids, which prevent graft rejection by nonspecific effects on lymphocyte function as well as generalized cytotoxicity to bone marrow cells.
FK 506, a second generation immunosuppressive drug, isolated from the fermentation broth of Streptomyces tsukubaensis (Kino et al., J. Antibiotics, 40:1249 (1987); Kino et al., J. Antibiotics, 40:1256 (1987)) has properties similar to Cyclosporin A, but at much greater potencies (Goto et al., Transplant. Proc., 19(5) Supp. 6:11 (1987); Ochiai et al., Transplant. Proc., 19:1284 (1987); Zeevi et al., Transplant. Proc., 22(1): 106 (1990)). Its stronger in vitro and ex vivo characteristics have been demonstrated using primary mixed lymphocyte cultures (MLRs) and secondary proliferation of alloreactive T cells propagated from organ transplantations, respectively (Zeevi et al., Transplant. Proc., 19(5) Supp. 6:40 (1987)). Although FK 506 is more potent than cyclosporin A, similar toxicity profiles to cyclosporin A have been reported and so the search will have to continue for the introduction of an equally effective, but less toxic, immunosuppressive drug.